5 research outputs found
Identification of SNAIL1 Peptide-Based Irreversible Lysine-Specific Demethylase 1‑Selective Inactivators
Inhibition
of lysine-specific demethylase 1 (LSD1), a flavin-dependent
histone demethylase, has recently emerged as a new strategy for treating
cancer and other diseases. LSD1 interacts physically with SNAIL1,
a member of the SNAIL/SCRATCH family of transcription factors. This
study describes the discovery of SNAIL1 peptide-based inactivators
of LSD1. We designed and prepared SNAIL1 peptides bearing a propargyl
amine, hydrazine, or phenylcyclopropane moiety. Among them, peptide <b>3</b>, bearing hydrazine, displayed the most potent LSD1-inhibitory
activity in enzyme assays. Kinetic study and mass spectrometric analysis
indicated that peptide <b>3</b> is a mechanism-based LSD1 inhibitor.
Furthermore, peptides <b>37</b> and <b>38</b>, which consist
of cell-membrane-permeable oligoarginine conjugated with peptide <b>3</b>, induced a dose-dependent increase of dimethylated Lys4
of histone H3 in HeLa cells, suggesting that they are likely to exhibit
LSD1-inhibitory activity intracellularly. In addition, peptide <b>37</b> decreased the viability of HeLa cells. We believe this
new approach for targeting LSD1 provides a basis for development of
potent selective inhibitors and biological probes for LSD1
Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding
Triazole
ureas constitute a versatile class of irreversible inhibitors
that target serine hydrolases in both cells and animal models. We
have previously reported that triazole ureas can act as selective
and CNS-active inhibitors for diacylglycerol lipases (DAGLs), enzymes
responsible for the biosynthesis of 2-arachidonoylÂglycerol (2-AG)
that activates cannabinoid CB<sub>1</sub> receptor. Here, we report
the enantio- and diastereoselective synthesis and structure–activity
relationship studies. We found that 2,4-substituted triazole ureas
with a biphenylmethanol group provided the most optimal scaffold.
Introduction of a chiral ether substituent on the 5-position of the
piperidine ring provided ultrapotent inhibitor <b>38</b> (DH376)
with picomolar activity. Compound <b>38</b> temporarily reduces
fasting-induced refeeding of mice, thereby emulating the effect of
cannabinoid CB<sub>1</sub>-receptor inverse agonists. This was mirrored
by <b>39</b> (DO34) but also by the negative control compound <b>40</b> (DO53) (which does not inhibit DAGL), which indicates the
triazole ureas may affect the energy balance in mice through multiple
molecular targets
In Vitro and in Vivo Evaluation of <sup>11</sup>C‑Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies
Monoacylglycerol
lipase (MAGL) is the principle enzyme for metabolizing
endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade
of MAGL increases 2-AG levels, resulting in subsequent activation
of the endocannabinoid system, and has emerged as a novel therapeutic
strategy to treat drug addiction, inflammation, and neurodegenerative
diseases. Herein we report a new series of MAGL inhibitors, which
were radiolabeled by site-specific labeling technologies, including <sup>11</sup>C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination.
The lead compound [<sup>11</sup>C]<b>10</b> (MAGL-0519) demonstrated
high specific binding and selectivity in vitro and in vivo. We also
observed
unexpected washout kinetics with these irreversible radiotracers,
in which in vivo evidence for turnover of the covalent residue was
unveiled between MAGL and azetidine carboxylates. This work may lead
to new directions for drug discovery and PET tracer development based
on azetidine carboxylate inhibitor scaffold
In Vitro and in Vivo Evaluation of <sup>11</sup>C‑Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies
Monoacylglycerol
lipase (MAGL) is the principle enzyme for metabolizing
endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade
of MAGL increases 2-AG levels, resulting in subsequent activation
of the endocannabinoid system, and has emerged as a novel therapeutic
strategy to treat drug addiction, inflammation, and neurodegenerative
diseases. Herein we report a new series of MAGL inhibitors, which
were radiolabeled by site-specific labeling technologies, including <sup>11</sup>C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination.
The lead compound [<sup>11</sup>C]<b>10</b> (MAGL-0519) demonstrated
high specific binding and selectivity in vitro and in vivo. We also
observed
unexpected washout kinetics with these irreversible radiotracers,
in which in vivo evidence for turnover of the covalent residue was
unveiled between MAGL and azetidine carboxylates. This work may lead
to new directions for drug discovery and PET tracer development based
on azetidine carboxylate inhibitor scaffold
In Vitro and in Vivo Evaluation of <sup>11</sup>C‑Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies
Monoacylglycerol
lipase (MAGL) is the principle enzyme for metabolizing
endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade
of MAGL increases 2-AG levels, resulting in subsequent activation
of the endocannabinoid system, and has emerged as a novel therapeutic
strategy to treat drug addiction, inflammation, and neurodegenerative
diseases. Herein we report a new series of MAGL inhibitors, which
were radiolabeled by site-specific labeling technologies, including <sup>11</sup>C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination.
The lead compound [<sup>11</sup>C]<b>10</b> (MAGL-0519) demonstrated
high specific binding and selectivity in vitro and in vivo. We also
observed
unexpected washout kinetics with these irreversible radiotracers,
in which in vivo evidence for turnover of the covalent residue was
unveiled between MAGL and azetidine carboxylates. This work may lead
to new directions for drug discovery and PET tracer development based
on azetidine carboxylate inhibitor scaffold